Opioids are classified into natural opioids (e.g., morphine), semi-synthetic opioids (e.g., heroin), synthetic opioids (e.g., methadone), and endogenous opioids (e.g., endorphins). See, e.g., Piestrzeniewicz et al., Postepy Biochem, 2006, 52:313-319.
They act in both central and peripheral nervous systems to produce various pharmacological effects including, among others, analgesia and decreased gastrointestinal motility. Opioids have long been used as the most effective analgesics for treating acute pain (e.g., post-operative pain) and chronic pain (e.g., cancer pain). See, e.g., Waldhoer et al., Annu Rev Biochem, 2004, 73:953-990.
Opioids primarily activate three classic subtypes of opioid receptors, namely, mu-opioid receptor (MOR), delta-opioid receptor (DOR), and kappa-opioid receptor (KOR). Various heterocyclic compounds have been used as nonselective or selective MOR agonists for treating an opioid receptor-associated condition, e.g., pain, immune function, esophageal reflux, and cough. Yet, conventional heterocyclic compounds typically produce adverse effects, such as respiratory depression. Moreover, long-term use of these compounds for controlling chronic pain develops severe side effects such as tolerance, dependence, and addiction. See, e.g., Tao et al., J Pharmacol Exp Ther, 2002, 303:549-556.
There is a need to develop new MOR modulators that have fewer and/or less deterious side effects for therapeutic use.